4-chloro-5-(2-methylene-butryl)-indole carboxylic acid

ABSTRACT

The production of 5-(2-methylene-alkanoyl)-benzofuran-, 5-(2methylene-alkanoyl)-indole- and 5-(2-methylene-alkanoyl)benzo(b)thiophene-2-carboxylic acids by reaction of the corresponding 5-(2-dimethylaminomethyl-alkanoyl)- derivatives with sodium acetate in glacial acetic acid and their pharmaceutically acceptable salts with bases, a method of producing a diuretic and saluretic effect in mammals comprising administering said compounds to said mammals and pharmaceutical compositions containing said compounds are described. A typical embodiment is 5-(2-methylene-butyryl)-6-methyl-benzofuran-2carboxylic acid.

United States Patent Zergenyi et al.

[451 Aug. 8, 1972 4-CHLORO-5-(2-METHYLENE- BUTRYLHNDOLE CARBOXYLIC ACID[73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: Aug. 19, 1970 [21] Appl. No.: 65,341

Related US. Application Data [62] Division of Ser. No. 746,262, July 22,1968,

Pat. No. 3,580,931.

[52] US. Cl. ..260/326.13 R [51] Int. Cl. ..C07d 27/56 [58] Field ofSearch ..260/326. 13 R [56] References Cited UNITED STATES PATENTS3,565,912 2/1971 Szmuszkovicz ..260/326. 1 6

Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. NarcavageAttorney-Karl F. Jorda and Bruce M. Collins [5 7] ABSTRACT Theproduction of 5-(Z-methylene-alkanoyl)-benzofuran-,5-(Z-methyIene-alkanoyl) indoleand 5-(2-methylene-alkanoyl)-benzo[b]thiophene-2-carboxylic acids by reaction ofthe corresponding 5-(2- dimethylaminomethyl-alkanoyl)- derivatives withsodium acetate in glacial acetic acid and their pharmaceuticallyacceptable salts with bases, a method of producing a diuretic andsaluretic efiect in mammals comprising administering said compounds tosaid mammals and pharmaceutical compositions containing said compoundsare described, A typical embodiment is5-(Z-methylene-butyryl)-6-methyl-benzofuran- 2-carboxylic acid.

1 Claim, No Drawings 4-CHLOR0-5-(2-METIIYLENE-BUTRYM-HNDOLE CARBOXYLICACID This application is a division of copending application Ser. No.746,262 filed July 22, 1968, now U.S. Pat. No. 3,580,931.

DETAILED DESCRIPTION The present invention pertains to heterocycliccarboxylic acids, processes for the production thereof, a method ofproducing a diuretic and saluretic effect as well as pharmaceuticalcompositions.

More particular, the present invention pertains to heterocycliccarboxylic acids of the Formula I COOII wherein R is hydrogen or loweralkyl;

X is oxygen, sulfur, the imino or the methylimino group;

Y is hydrogen, methyl, fluoro, chloro or bromo, and each of Z and Ztaken individually is hydrogen, lower alkyl,lower alkoxy, fluoro, chloroor bromo;

as well as to the pharrnaceutically acceptable salts thereof with abase.

These compounds have been found to possess valuable pharmacologicalproperties. In particular, they have a diuretic and saluretic activity.These properties characterize the compounds of the invention suitablefor the treatment of disturbances which are due to insufiicientexcretion of urine and of electrolytes, especially of sodium chloride.Such disturbances are the cause of oedema and hypertension. The newsubstances administered orally in low doses increase the excretion ofuria and of sodium and chlorine ions to a considerable extent.

In the heterocyclic carboxylic acids of Formula I, Z, occupies the 4- or6-position and Z the 6- or 7-position of the heterocyclic ring. By theterm lower alkyl and the derivation thereof using the root alk, namelyalkoxy, is intended a group comprising a straight or branchedhydrocarbon chain of from one to four carbon atoms. Representative oflower alkyl groups are thus, e.g. the methyl, ethyl, propyl, isopropyl,butyl or tert. butyl group. Embraced by the term lower alkoxy are suchgroups as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or the sec.butoxy group.

Compounds of Formula I are produced according to a first process bydecomposing a compound of Formula II COOH Z2 (II) wherein R, X, Y, Z,and Z have the meanings given in Formula I, and Am is the radical of asecondary amine, in which said secondary amine of Formula Ill H-Am (Ill)wherein Am is split off. If desired, the reaction product of Formula Iis converted into a pharmaceutically acceptable salt with an inorganicor organic base in a conventional manner.

As radical of a secondary amine, Am can be, e.g. the dimethylamino,diethylamino, l-pyrrolidino, lpiperidino, l-hexahydro- 1 I-l-azepino orthe morpholino group.

A compound of Formula II is preferably decomposed by heating in thepresence of a weak base in a solvent containing hydroxyl groups.Examples of weak bases are sodium acetate or sodium hydrogen carbonate.Examples of solvents containing hydroxyl groups are glacial acetic acidand water.

Compounds of Formula II are produced, for example, as follows:Carboxylic acids of Formula IV, which are also starting materials forthe second process according to the invention, are condensed accordingto Friedel-Crafts in the presence of aluminum chloride in nitrobenzenewith carboxylic acid chlorides of Formula IVa R-CH COCI W8) wherein Rhas the meaning given in Formula I, to form the corresponding S-alkanoylderivatives. Such 5-alkanoyl derivatives are, e.g. the S-acetyl,5-propionyl, 5- butyryl, 5-valeryl or 5-isovaleryl derivatives ofbenzofuran-Z-carboxylic acid, of benzo[b]thiophene-2-carboxylic acid, ofindole-Z-carboxylic acid or of l-methyl-indole-2-carboxylic acids which,optionally are substituted by the radicals Y, Z and/or Z The S-alkanoylderivatives mentioned are then converted into the corresponding Mannichderivatives with the aid of formaldehyde or paraformaldehyde and asecondary organic amine.

Compounds of Formula I are produced by a second process according to theinvention by reacting, according to Friedel-Crafts, a compound ofFormula IV J-COOH X wherein X, Y, Z, and Z have the meanings given inFormula I, with a carboxylic acid halide of Formula V Z2 (IV) Basia.

or with a carboxylic acid anhydride of Formula VI verted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

As halogen, Q is preferably chlorine or bromine. Suitable catalysts forthe reaction according to Friedel- Crafts are, e.g. aluminum chloride,stannic chloride, zinc chloride, concentrated sulfuric acid, phosphoricacid, polyphosphoric acid or pyrophosphoric acid, containing hydroxylgroups. The acids are used preferably, when a carboxylic acid anhydrideis the acylating agent. The reaction is preferably performed in asolvent, such as, e.g. aliphatic or cycloaliphatic hydrocarbons such asheptane or cyclohexane, nitrated hydrocarbons such as nitromethane,nitrocyclohexane or nitrobenzene, halogenated hydrocarbons such ascarbon tetrachloride, ethylene chloride, methylene chloride, oro-dichlorobenzene, and carbon disulfide.

Compounds of Formula II wherein X, Y, Z and 2, have the meanings givenin Formula I are described in the literature, e.g.benzofuran-Z-carboxylic acid [cf. R. Fittig et al., Ann. Chem. 216, 162(1883)], benzo[b]thiophene-Z-carboxylic acid [cf. P. Friedlander et al.,Chem. Ber. 45, 2087 (1912)], indole-2-carboxylic acid [cf. W. Madelung,Chem. Ber. 45, 3521( 1912)], 4-chloroindole'2-carboxylic acid (cf. H.N.Rydon et al., J. Chem. Soc. 1955, 3499) and lmethyl-indole-Z-carboxylicacid [cf. E. Fischer et al., Chem. Ber. 16, 2245 1883)]. Other compoundsof this type can be produced in analogy to the literature referencescited.

Compounds of Formula I are produced by a third process according to theinvention by simultaneously saponifying the ester group and splittingoff the secon dary organic amine from a compound of Formula VII (VII)wherein R, X, Y, Z, and Z have the meanings given in Formula I, Am hasthe meaning given in Formula II and R is a lower alkyl or the benzylgroup. If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

This simultaneous saponification and splitting reaction is preferablyperformed by shortly boiling the compound of Formula VII in an aqueousalkanol in the presence of an alkali or alkaline earth metal hydroxideor carbonate.

Compounds of Formula VII, are produced e.g. by esterifying a compound ofFormula II with a lower alkanol or benzyl alcohol. This esterificationhas to be carried out under mild conditions so that the secondary aminogroup is not split off. The compounds of Formula VII are also producedby acylating according to Friedel-Crafts a lower alkyl or benzyl esterof Formula IV with an acid chloride of Formula IVa. The so obtainedester is then converted into the corresponding Mannich derivative ofFormula VII by reaction with formaldehyde or paraformaldehyde and asecondary amine.

Compounds of Formula I are produced by a fourth pmcess according to theinvention by saponifying in conventional manner a compound of FormulaVIII X -COORr Z2 (VIII) wherein R, X,'Y, Z and Z have the meanings givenin Formula I and R, has the meaning given in Formula VII.

If desired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base inconventional manner.

This saponification is,-e.g., carried out in a solvent containinghydroxyl groups in the presence of an alkali or alkaline earth metalhydroxyde or carbonate.

Compounds of Formula VIII are produced by heating a compound of FormulaVII in the presence of a weak base, in a solvent containing hydroxylgroups, in a way as described inthe first process of this invention.Sodium acetate and sodium hydrogen carbonate which do not saponify theester function can be used as weak bases. Water or lower fatty acidssuch as glacial acetic acid can be used as solvents.

Compounds of Formula I are produced by a fifth process according to theinvention by splitting off hydrogen halide from a compound of Formula IXCOOH wherein R, X, Y, Z and Z have the meanings g'ven in Formula I and Qhas the meaning given in Formula V. If desired, the reaction product ofFormula I is converted into a pharmaceutically acceptable salt with aninorganic or organic base in a conventional manner.

As halogen atom Q is preferably chlorine or bromine. The elimination ofhydrogen halide is carried out e.g. by boiling the compound of FormulaIX in an organic base, such as collidine or in dimethyl formamide.Hydrogen halide can also be eliminated by boiling a compound of FormulaIX in an organic solvent such as benzene or toluene in the presence ofsilver acetate or by boiling in dimethyl formamide in the presence oflithium bromide or carbonate.

The compounds of Formula IX used as starting materials can be producedin analogy to the second process of this invention by condensing acompound of Formula IV, according to Friedel-Crafts, in nitrobenzene inthe presence of aluminum chloride, with a carboxylic acid chloride ofFormula IXa wherein R has the meaning given in Formula I and Q themeaning given in Formula V. The compounds of Formula IX can also beproduced by chlorinating or brominating a compound of Formula IXb CH3 Z]wherein R, X, Y, Z and Z have the meanings given in Formula I. Theproduction of the compounds of Formula IXb is described in the firstprocess of this invention. The chlorination or bromination is, e.g.carried out by adding the equimolar amount of chlorine or bromine to thestirred solution of the compound of Formula IXb in an appropriatesolvent such as glacial acetic acid,'nitrobenzene or a halogenatedhydrocarbon.

Compounds of Formula I are produced by a sixth process according to theinvention by treating a compound of Formula X cups-a, z,

nrr-oo Y X/COOH wherein R, X, Y,Z, and Z have the meanings given inFormula I and R represents a lower alkyl group with an alkylating agentof Formula Xa R A (Xa) wherein R has the meaning given in Formula X andA is the monovalent anion of a mineral acid, to give the ternarysulfonium compound of Formula Xb A9 I -o 0 OH V .7 Z2 .7 LXI wherein R,X, Y, Z and Z have the meanings given in Formula I, R has the meaninggiven in Formula X and A the meaning given in Formula Xa, and boilingthis compound in the presence of a weak base until the sulfonium groupis split off. Ifdesired, the reaction product of Formula I is convertedinto a pharmaceutically acceptable salt with an inorganic or organicbase in a conventional manner.

Alkyl halides and dialkylsulfates can be used as alkylating agents. Theelimination of the ternary sulfonium group is performed under similarconditions as the elimination of the secondary amine as described in thefirst process of this invention, i.e. by heating the compound of FormulaXb in the presence of a weak base such as sodium acetate or sodiumhydrogen carbonate in a solvent containing hydroxyl groups like water orlower fatty acids. The compounds of Formula X can be produced e. g. byboiling, in a bufl'ered aqueous solution of pH 7-9, a compound ofFormula II, of a salt of such a compound with a hydrogenhalide, with anexcess of a sodium lower alkyl sulfide of the Formula Xc Na-S-R (Xc)wherein R has the meaning given in Formula X, until thesecondary amineis replaced by the alkylsulfide group.

Compounds of Formula I are produced by a seventh process according tothe invention by splitting off the alkylsulfonyl group of a compound ofFormula XI Z2 (XI) wherein R, X, Y, Z and Z have the meanings given inFormula I and R has the meaning given in Formula X, by boiling thiscompound in the presence of a weak base in a solvent containing hydroxylgroups. Ifdesired, the reaction product of Formula I is converted into apharmaceutically acceptable salt with an inorganic or organic base in aconventional manner.

Sodium acetate or sodium hydrogen carbonate can be used as weak bases.As solvents are preferably used water or lower fatty acids.

The compounds of Formula XI can be easily produced by treating acompound of Formula X in an organic solvent with a per acid or hydrogenperoxide. Per acids suitable for this oxidation are, e.g., performicacid peracetic acid or perbenzoic acid. Lower alcohols, lower ketones orlower fatty acids are convenient solvents for this reaction.

For the formation of phannaceutically acceptable I salts can be usedinorganic or organic bases such as alkali'or alkaline earth hydroxides,carbonates or bicarbonates. Suitable are thus, e.g. sodium, potassium,magnesium and calcium hydroxides, carbonates or bicarbonates, as well-ascholine and triethanolamine. Such salts are produced e.g. by mixing thecompound of Formula I with the equivalent amount of the desired base ina suitable solvent such as water, mixtures of water with an organicsolvent or in organic solvents alone such as methanol, ethanol orpropanol and isolating the salts formed in a conventional manner. I

The compounds of the invention have been found to have valuablepharmacological properties, especially diuretic and saluretic activitiescombined with a very low, order of toxicity. These favorable propertiesrender thecompounds of Formula I and their pharmaceutically acceptablesalts with inorganic or organic bases suitable for the treatment ofdisturbances which are due to insufficient excretion of urine and ofelectrolytes, particularly of sodium chloride. Such disturbances are thecauses of oedema and hypertension.

The diuretic and saluretic effects of the compounds of the invention areillustratively demonstrated in dogs and rabbits. Thus it can be shown byconventional pharmacological experiments thatS-(Z-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid, 5-(2-methylene-butyryl)-4-chloro-indole-2-carboxylic acid and5-(2-methylene-butyryl)-4-chloro-benzo[b]thiop hene-Z-carboxylic acidadministered orally or parenterally in amounts of 5 mg/Kg to dogs andrabbits increase the excretion of urine and simultaneously of sodiumchloride to a considerable extent, whereby no undesirable side efl'ectsare observed.

The new active substances or the pharmaceutically acceptable saltsthereof are preferably administered orally.

The daily dosages vary between 50 and 1,000 mg for mammals. Suitabledosage units such as dragees and tablets, preferably contain 25-500 mlof an active substance according to the invention, i.e. 20 to percent ofa compound of Formula I. They arev produced by combining the activesubstance, e.g. with solid pulverulent carriers such as lactose,saccharose, sorbitol, mannitol; starches such as potato starch, maizestarch or amylopectin, also laminaria powder or citrus pulp with theaddition of lubricants such as magnesium or The temperatures are givenin degrees Centigrade. I

these coatings, e.g. to distinguish between'varying I dosages'of activesubstance. The following examples further illustrate the production ofthe new compoundsof Formula I and of hitherto undescribed intermediate,products .as "well as 1 the production of pharmaceutical compositionsbut they are by no means the'sole methods'of producing same.

a. 2.3 of butyryl-benaofuran-2-carboxylic acid;

0.5 g of paraformaldehyde and 1.0. g-of dimethylamine hydrochloride areslurried in ml of dioxan and the whole is refluxed.forhour'swhilestirring. The reaction mixtureis'. cooled andevaporatedtodryness in vacuo. 30 ml of glacial acetic acidand 3.0g ofanhydrous sodium acetate added tothe crude 5-(2-Idimethyl-ar'n'inoniethyl-butyry l)-benzoturan-2-carboxylic'acidhydrochloride obtained and the mixture is refluxed for 2'hours. Thesolvent is thenevaporated in vacuo, the residue is taken up in 50 ml ofwater and the "aqueous solution is acidified with concentratedhydrochloric acid topl l 2 -3. The hydrochloric acid suspension isstirred for half an hour. The precipitated crystals are thenfilteredofi', washed withwater, dried invacuoiat 60-and recrystallizedfrombenzene/hexane. The S-(Z-methyIenebutyryI)-b nZ0furan-2carboxylicacid obtained meltsat l28 -'l 29.

.The S-butyryI-ben'mfuran-LcarbOxyIic acid used as starting material isproduced as follows:

20 ml of nitroben'zene and the-suspension is cooled to suspension iscooled to..0fand 8 got 2-methylene butyryl chloride are added all atvonceLThemixture is heatedto within 20 minutes, stirredfor 45 minutes atthistemperature and then poured onto 200 g ofice and ml of concentratedhydrochloric acid. The hydrochloric acid suspension is extracted twicewith 100 ml of ether each time. The 'etherextract is washed with waterand extracted twice with-50 mlof concentrated sodium hydrogen carbonatesolution each time.

The sodium hydrogen'carbonate solution is acidified with concentratedhydrochloric acid to pH 2-3 and'the precipitated crude productis'extracted withether. The ether solution is dried overmagnesiumsulphate, concentrated and the residue is purified bychromatography on silica gel using benzene/ether/glacial aceticacid(900:80 :20)' ias eluent. The 4-chloro-5-(2methylene-butyryl)-indole-2-carboxylic. acid obtainedmeltsatl9l9-.l9l2.- f I EX PLEQ.

- a. Crude 'mamaszaimem laan mtm l:

butyryl)'-indole-2-carboxylic acid hydrochloride .is obtainedanalogously tov example 1(a) starting from 3 4- dichloro- 5-butyryl)-ir|dole-Z- carboxylic acid 7 with Pa formaldehyde anddimethylamine hydrochloride. It is converted v with sodium acetate and,glacial acetic acid into..3,4-dichloro 5-(2methylene butyryl)-indoleb:5.0 g 'of benzofuran-2-c arboxylic acidIcf. Fimg; et. al., Ann. Chem. '21'6, 162 (1889)] are suspended in 0,: 12.0 g of pulverizedaluminum'chloride are added in portions tothissuspension so that thetemperature of v the reaction mixture 'does not rise. above 10, 4.0g ofbutyryl chloride are then added all at-ion'ce. The mixture is thenheated to' room temperature while stirring. Stirring iscontinued'for .24hours at this temperature and then it is poured onto 100 glof icein 20ml of concentrated hydrochloric acid. The hydrochlon'cacid suspension isextracted twice with 100 ml of acetic acid ethyl estereach time, theacetic acid ethyl ester solution is'washed with 50 ml of water andextracted twice with 50 ml of concentrated sodium hydrogen carbonatesolution each time. The pH of the sodium hydrogen carbonate solution isadjusted to 3 with concentrated hydrochloric acid, the mixture isstirredfor 30 minutes,

the precipitated crude product is filtered off, the filter residueis'd'ried in vacuo at 60 and recrystallized from g of pulverizedaluminum chloride are added in portions so that the, temperature neverexceeds 10. The

2-.carboxylic' acid which, recrystallizes from benzene/acetic acid ethylester, melts at.2l0-2l 1. The starting material, 3.,4-dichloro Sbutyryl-indole-2- carboxylic acid, is producedasfollow's:

' b. .29 got 4-chloroind0le- 2-.-carboxylic acid (of. H.N. Rydonet-val., J. Chem. Soc. 1955', 3499) are suspended in 400 nil of ether.15 ml of sulphurylchloride are added, dropwise to this suspension atreflux, tempera mm,- the addi'tion being made within20 minutes whilestirring. The reaction mixture is stirred for another 3 hours at thesame temperature, then cooled and 100 ml of water are a rlded dropwise.The ether solution .is separated from the aqueoussolution, the organicphase is washed withwater and. extracted twice with 100 ml of saturatedsodium hydrogen carbonate solution each time; The sodium hydrogen.carbonate" solution is .acidified with concentrated hydrochloric acid topH 2 and the precipitated free carboxylic acid is filtered off,

washed with water and dried in vacuoat 60. Recrystallization frombenzene/acetic acid ethyl ester yields pure .3,4-dichloro indole-2carboxylic acid which melts at 24,024 1. c. l 1.5 g of the carboxylicacid obtained according to (b) are suspended in 50 ml of nitrobenzene,7.5 g of butyryl chloride are added to this suspension, the mixture iscooled to 0 and "25 g of pulverized aluminum chloride are added inportions so that the temperature of the reaction mixture does not exceed10. The whole is then stirred for another 5 hours at a reactiontemperature of 25.'The reaction solution is vthen poured {onto 200 g ofice in 40 mlof concentrated hydrochloric acid, mlof benzene are addedand the suspension is at 60 in vacuo and recrystallized from dioxan. The3,4-

-dichloro-S-butyrl-indole-2-carboxylic acid obtained meltsat271?-272.

a. Crude l-methyl-3,4-dichloro--(2-dimethylaminomethyl-butyryl)ndole-2-carboxylic acid hydrochloride isobtained analogously to example 1 a) starting from crude1-methyl-3,4-dichloro5-butyryl-indole-2-carboxylic acid withparaformaldehyde and dimethylamine hydrochloride. The crude product isconverted with glacial acetic acid and sodium acetate intol-methyl-3,4-dichloro-5-(2-methylene-butyryl)- indole-2-carboxylic acid.M.P. l63164 (from benzene).

The starting material,l-methyl-3,4-dichloro-5-butyryl-indole-Z-carboxylic acid, is produced asfollows:

b. 29 g of 4-chloroindole-2-carboxylic acid (cf. l-LN. Rydon et al., J.Chem. Soc. 1955, 3499) are dissolved by gently heating in 300 ml ofacetone. 35 ml of dimethyl sulphate are added to this solution and themixture is added dropwise within 30 minutes while stirring to a lightlyboiling suspension of 45 g of finely pulverized potassium carbonate in150 ml of acetone. The whole is stirred under reflux for another 3hours. The precipitated salts are then removed from the solution byfiltration and the filtrate is concentrated in vacuo. Crudel-methyl-4-chloroindole-2-carboxylic acid methyl ester remains, to whichare added 75 ml of 4N sodium hydroxide solution, 75 ml of water and 50ml of ethanol. The mixture is refluxed for 30 minutes, cooled, washedwith ether and acidified to pH 2 with concentrated hydrochloric acid.The precipitated crystals are filtered off, washed with water and driedin vacuo at 70. The crude product is recrystallized from dioxan,whereupon the l-methyl-4-chloroindole-2-carboxylic acid melting at252-253 is obtained.

The carboxylic acid obtained is converted with sulphuryl chlorideanalogously to example 3(b) into 1-methyl-3,4-dichloro-indole-2-carboxylic acid M.P.

252-253 (from dioxan) which is reacted with butyryl EXAMPLE 5 a. Crude4-methyl-5-(Z-dimethylaminomethyl-butyryl)-benzofuran-2-carboxylic acidhydrochloride is obtained analogously to example 1a) starting from 4-methyl-5-butyryl-benzofuran-2-carboxylic acid with paraformaldehyde anddimethylamine hydrochloride. The crude product is converted with sodiumacetate in glacial acetic acid into 4-methyl-5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid which melts. at l50160(from benzene/ acetic acid ethyl ester).

The starting material, 4-methyl-5-butyryl-benzofuran-Z-carboxylic acid,is produced as follows:

b. A suspension of 11 g of 2-methyl-6-hydroxybenzaldehyde [cf. 0.Anselmino, Chem. Ber. 50, 395 (1917)]and l l g of anhydrous potassiumcarbonate in 40 ml of methylethyl ketone is stirred, refluxed and,within 15 minutes, 20 g of bromomalonic acid diethyl ester are addeddropwise. The reaction mixture is then boiled and stirred for another 7hours and then concentrated in vacuo. A solution of 10 g of potassiumhydroxide in 8 ml of water and 80 ml of ethanol is added to the residue,the reaction mixture is refluxed for 2 hours, cooled, 100 ml of waterare added and the ethanol is evaporated in vacuo. The resultantalkaline-aqueous solution is acidified to pH 2-3 with 20 percentsulphuric acid. The precipitated crystalline crude product is filteredoff, washed with water, dried in vacuo at 60 and re-crystallized frombenzene whereupon the pure 4-methyl-benzofuran-2-carboxylic acid meltsat 18919l.

The carboxylic acid obtained is converted into 4-methyl-S-butyryl-benzofirran-Z-carboxylic acid, M.P. 165l67 (frombenzene) with butyryl chloride in the presence of aluminum chlorideanalogously to example 1(b).

EXAMPLE 6 4-methyl-5-( Z-methyIene-butyryl )-indole-2-carboxylic acid,M.P. l94-195 (from benzene) is obtained analogously to example 2(a) from4-methyl-indole-2- carboxylic acid [cf. R. Andrisano at al., CA 52, 6313(1958): Gazz. chim. ital. 87, 949 (1957)] with 2- methylene-butyrylchloride in the presence of aluminum chloride in nitrobenzene.

EXAMPLE7 a. l,4-Dimethyl-5-(Z-methyIene-butyryl)-indole-2- carboxylicacid, M.P. l1 8 1 (from acetic acid ethyl ester/benzene) is obtainedanalogously eo to 2(a) from 1,4-dimethyl-indole-2-carboxylic acid and 2-methylene-butyryl chloride in the presence of aluminum chloride innitrobenzene.

The starting material, 1,4-dimethyl-indole-2-carboxylic acid, isproduced as follows:

b. A suspension of 35 g of potassium carbonate in ml of acetone isstirred at reflux temperature. A solution of 17.5 g of4-methyl-indole-2-carboxylic acid [cf. R. Andrisano et al., Gazz, chim.ital. 87,949 (1957)]and 25 ml of dimethyl sulphate in 150 ml of acetoneis added dropwise to. this suspension within 20 minutes. The reactionmixture is refluxed for 14 hours, cooled, the precipitate is filteredoff and washed with acetone. The filtrate is concentrated in vacuo. Theresidue, crude 1,4-dimethyl-ihdole-Z-carboxylic acid methyl ester, isrefluxed for 30 minutes with ml of 2N sodium hydroxide solution and 60ml of ethanol. The solution is then cooled, the pH is adjusted to 2 andthe precipitated crude carboxylic acid is filtered off, washed withwater and dried in vacuo at 60. After recrystallization from acetic acidethyl ester/dioxan, l,4-dimethyl-indole-2-carboxylic acid, MP. 236-237,is obtained.

EXAMPLE 8 a. 4.0 g of S-butyryl-6-methyl-benzofuran-2-carboxylic acid,0.82 g of paraformaldehyde and 1.64 g of dimethylamino hydrochloride arerefluxed for 5 hours in 40 ml of dioxane while stirring. The reactionmixture is then evaporated in vacuo. 5.0 g of sodium acetate as well as50 ml of glacial acetic acid are added to the crude5-(Z-dimethylaminomethylbutyryl)-6-methylbenzofuran-Z-carboxylic acidhydrochloride obtained and the mixture is refluxed for 2 hours. Theglacial acetic acid is then evaporated in vacuo, the residue is taken upin 100 ml of water and the aqueous solution is acidified withconcentrated hydrochloric acid to pH 2-3. The hydrochloric acidsuspension is stirred for 1 I acid hour at 20. The precipitated crystalsare then filtered off under suction, dissolved in acetic acid ethylester, the solution is dried with anhydrous magnesium sulphate andevaporated in vacuo. The residue is recrystallized from a small quantityof acetic acid ethyl ester whereupon-(2-methylene-butyryl-6-methylbenzofuran-2-carboxylic acid is obtained,M.P. 141-142.

The starting compound, 5-butyryl-6-methyl-benzofuran-Z-carboxylic acid,is produced as follows:

b. 10.0 g of 6-methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers,Ann. Chem. 408, 255 (1915)] are suspended in 30 ml of nitrobenzene. 28.0g of aluminum chloride are added to the suspension in portions whilecooling with ice so that a reaction temperature of is maintained. 9.0 gof butyryl chloride are then added dropwise within 30 minutes at thesame temperature. The mixture is then stirred for 24 hours at 25, afterwhich it is poured into 300 g of ice and 50 m] of concentratedhydrochloric acid and the hydrochloric acid suspension is extractedtwice with 300 ml of ether each time. The combined ether solutions arewashed with water and extracted twice with 100 ml of saturated sodiumhydrogen carbonate solution each time. The pH of the sodium hydrogencarbonate extract is adjusted to 2-3 with concentrated hydrochloric acidand the suspension formed is stirred for 1 hour at room temperature. Theprecipitated crystals are filtered off under suction, washed with waterand dissolved in acetic acid ethyl ester. The acetic acid ethyl estersolution is dried with anhydrous magnesium sulphate and concentrated invacuo. Fractional recrystallization of the residue from acetic acidethyl ester/dioxane yields 5-butyryl-6-mcthyl-benzofuran-2- carboxylicacid, M.P. 155-15 7.

EXAMPLE 9 a. Starting from 4.6 g to 4,6-dimethyl-5-butyrylbenzofuran-2carboxylic acid, 1.0 g of paraformaldehyde and 1.75 g of dirnethylaminehydrochloride, crude 4,6-dimethyl-5-(2dimethyl-aminomethyl-butyryl)-benzofuran-2-carboxylic acid hydrochloricis obtained analogously to example 1(a). It is converted with 5.0 g ofsodium acetate and 50 ml of glacial acetic acid into4,6-dimethyl-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid whichmelts at 208-2 10 (from ethanol).

b. The starting compound, 4,6-dimethyl-5-butyrylbenzofuran-Z-carboxylicacid, is produced analogously to example 1(b) from 12.3 g of4,6-dimethyl-benzofuran2-carboxylic acid (cf. F.M. Dean et al., J. Chem.Soc. 1953, 1250-1261) and 10.0 g of butyryl chloride with 25.0 g ofaluminum chloride. After recrystallization from benzene/hexane, the4,6-dimethyl-5-butyrylbenzofuran-Z-carboxylic acid melts at l90-192.

EXAMPLE 10 a. Starting from 5.6 g of 4-chloro-5-butyryl-benzo[b]thiophene-2-carboxylic acid with 1.2 g of paraformaldehyde and 2.5 gof dimethylamine hydrochloride, crude4-chloro-(Z-dimethyl-aminomethyl-butyryl)- benzo[b]thiophene-2carboxylic acid hydrochloride is obtained analogously to example 1(a).It is converted with 1.7g of sodium acetate and 17 ml of glacial aceticinto 4-chloro-5-(2-methylene-butyryl)- benzo[blthiophene-Z-carbdxylicacid which melts at 239-24 1 (from ethyl acetate/dioxane).

The 4-chloro-5-butyryl-benzo[b]thiophene-2-carv boxylic acid used asstarting material is produced as follows:

b. 22.5 g of o-chlorobenzaldehyde are added dropwise within -1O minutesto a boiling mixture 20.0 g of rhodanine, 37.5 g of anhydrous sodiumacetate and 100 ml of glacial acetic acid. The reaction mixture is thenstirred for another 20 minutes at the same temperature temperature for10 minutes. The solution is cooled to 10 and 65 ml of concentratedhydrochloric acid are added. The crude o-chloro-a-mercapto-cinnamic acidprecipitates. The crude product is filtered off under suction, washedwith water and dissolved in 700 ml of ether. The ether solution is driedwith anhydrous magnesium sulphate and evaporated in vacuo. The residueis added in portions to a solution of 60 g of iodine in 200 ml ofnitxobenzene which has been heated to 180, the addition being madewithin 2 minutes. The reaction mixture is stirred for another 2 minutes,then poured onto 1 kg of ice and the suspension obtained is extractedtwice with 500 ml of chloroform each time. The chloroform extract isshaken twice with 100 ml of 2N sodium hydroxide solution each time, theaqueous alkaline solution is decolored with active charcoal andsaturated sodium sulphite solution, the suspension is filtered and thepH of the filtrate is adjusted with concentrated hydrochloric acid to2-3. The crude carboxylic acid precipitates. It is filtered off undersuction, washed with water and recrystallized from dioxane/acetic acidethyl ester, whereupon the pure 4-chlorobenzo[b] thiophene-2carboxy1icacid obtained melts at 24624 7.

c. 9.0 g of the carboxylic acid obtained according to (b) are convertedanalogously to example 1(b) into 4- chloro-5-butyryl-benzo[b]thiophene2-carboxylic acid which melts at 217219 (from acetic acid ethyl ester).The conversion is performed according to Friedel-Crafts with 8.0 g ofbutyryl chloride in the presence of 25.0 g of aluminum chloride.

EXAMPLE 11 a. Crude 6-methyl-5-[(2-dimethylaminomethyl)- nitrobenzene.After recrystallization from dioxane, it melts at 180-l 82.

EXAMPLE 12 a. Crude 6-methyl-5-[(2-dimethylaminomethyl)-valeroyl]-benzofuran -2-carboxylic acid hydrochloride is obtainedaccording to example 8(a) starting from 6-methyl-S-valeroyl-benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride. It is converted with sodiumacetate inglacial acetic acid into6-methyl-5-(Z-methyIene-valeroyl)-benzofuran-Z-carboxylic acid. M.P.l60162 (recrystallized from benzene/ethyl acetate).

b. The starting material, 6-methyl-5-valeroylbenzofuran-Z-carboxylicacid is produced analogously to example 8(b) from6-methyl-benzofuran-2-carboxylic acid (of. K. von Auwers, Ann. Chem. 408(1915) 255) with v'aleroyl chloride and aluminum chloride innitrobenzene. It melts at 154155 (recrystallized from acetic acid ethylester).

EXAMPLE, 13

a. Crude 6-methyl-5-[2-dimethylaminomethyl-3-methyl-butyryl]-benzofuran-2-carboxylic acid dihydrochloride is obtainedanalogously to example 1(a) starting from 6-methyl-5-(3-methyl-butyryl)-benzofuran-2-carboxylic acid with paraformaldehyde and dimethylaminehydrochloride. It is converted with sodium acetate in glacial aceticacid into 6- methyl--(2methylene-3-methyl-butyryl)-benzofuran-2-carboxylic acid, M.P. 3"" l54frecrystallized from acetic acid ethyl ester).

b. The starting compound,6-methyl-5-(3-methyl-butyryl)-benzofuran-2-carboxylic acid, is producedanalogously to example 8(b) from 6-methyl-benzofuran-Z-carboxylic acid(cf. K. von Auwers, Ann. Chem. 408 (1915) 255) with, isovaleroylchloride and aluminum chloride in nitrobenzene. It melts at 154156(recrystallized from ethyl acetate).

EXAMPLE l4 crude 6-methoxy-5-[(2-dimethylaminomethyl)-propionyl]-benzofuran-2-carboxylic acid hydrochloride is obtainedanalogously to example 8(a) starting fromvG-methoxy-5-propionyl-benzofuran-2- carboxylic acid, paraformaldehydeand dimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into6-methoxy-5-(2-methylenepropionyl)-benzofuran-2-carboxylic acid, M.P.l65167 (recrystallized from benzene).

b. The starting compound, 6-methoxy-5-propionylbenzofuran-Z-carboxylicacid, is produced analogously to example 8(b) from6-methoxy-benzofuran-2 carboxylic acid (cf. W. Will and P. Beck, Ber.19, 1777(1886) with propionyl-chloride and aluminum chloride innitrobenzene. It melts at 218-220 (recrystallized from ethyl acetate).

1 EXAMPLE 1s a. Crude 6-methoxy-5-[(2-dimethylaminomethyl)-butyryl]-benzofuran-2-carboxylic acid hydrochloride is obtainedanalogously to example 8(a) starting from 6-methoxy-S-butyryl-benzofuran-2-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride.

It is converted with sodium acetate in glacial acetic acid into6-methoxy-5-(Z-methyIene-butyryl)-benzofuran-Z-carboxylic acid, M.P.l53-154 (recrystallized from benzene).

b. The starting compound, 6-methoxy-5-butyrylbenzofuran-2-carboxylicacid is produced from 6- methoxy-benzofuran-Z-carboxylic acid (cf. W.Will and P. Beck, Ber. 19, 1777 (1886) with butyryl chloride andaluminum chloride in nitrobenzene. It melts at 1'89-l90 (recrystallizedfrom ethyl acetate).

EXAMPLE 16 5 to example 8(b) from 6-ethoxy-benzofuran-2-carboxylie acid(cf. W. Will and P. Beck, Ber. 19 (1886) 1777) with butyric acidchloride and aluminum chloride in nitrobenzene. The compound melts at203-205 recrystallized from ethanol). 4

EXAMPLE 17 I a Crude6-ethyl-5-[(2-dimethylaminomethyl)-butyryl]-benzofi1ran-2-carboxylicacid hydrochloride is obtained analogously to example 8(a) from6-ethyl-5- butyryl-benzofuran-Z-carboxylic acid, paraformaldehyde anddimethylamine hydrochloride. It is converted with sodium acetate inglacial acetic acid into 6-ethyl-5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid. M.P. 12l-l22(recrystallized from benzene).

b. The starting compound, 6-ethyl-5-butyrylbenzofuran-2-carboxylic acidis produced analogously to example 8(b) fromG-ethyl-benzofuran-Z-carboxylic acid with butyric acid chloride andaluminum chloride in nitrobenzene.6-Ethyl-5-butyryl-benzofuran-2-carboxylic acid melts at 152 153(recrystallized from acetic acid ethyl ester).

6-Ethyl-benzofuran-2-carboxylic produced as follows:

c. 50.0 g of m-ethylphenol, 55.0 g of malic acid and 100 ml ofconcentrated sulphuric acid are slowly acid is also heated to 130 whilestirring andstirring is-continued at this temperature for 20 minutes.The reaction mixture is then poured onto 2 kg of ice and extracted twicewith 500 ml of ether each time. The combined ether extracts are washedwith 200 ml of water and 200 ml of concentrated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated. Theresidue, crude 7-ethyl coumarin, is used as crude product.

d. 30.4 g of 7'ethyl coumarin are dissolved in 40 ml of chloroform and29.0 g of bromine in 20 ml of chloroform are added dropwise whilestirring. The temperature of the reaction mixture is kept between 20 and5 by occasional cooling in an ice bath. The reac tion mixture is thenstirred for another 20 minutes at room temperature and concentrated at50 under reduced pressure. The residue is added in portions to asolution of 80.0 g of potassium hydroxide in 160 ml of ethanol, whichsolution has been heated to 30, and the reaction temperature is kept at30-40 by cooling. The reaction mixture is then stirredfor 30 minutes atroom temperature and for 30 minutes at room temperature EXAMPLE 1:; i

a. Crude6-chloro-5-[(2-dimethylaminomethyl)-butyryll-benzofi1ran-2-carboxylicacid is obtained analogously to example 8(a) starting from 1.0 g of 6-chloro--butyryl-benzofuran-2-carboxylic acid, 0.16 g

of paraformaldehyde and 0.385 g of dimethylamine hydrochloride. It isconverted with sodium acetate in glacial acetic acid. into5-(2-methylene-butyryl)-'6- chloro-benzofuran-Z-carboxylic acid.Recrystallized from benzene/acetic acid ethyl ester, it melts at Thestarting compound, 6-chloro6-butyryl-benzofuran-2-carboxylic acid, isproduced as follows:

b. 80 g. of 2-chloro-4-hydroxy-butyrophenone (of.

Belgian Pat. No. 612,755) are slurried in 400 ml of water, and 100 ml of4N sodium hydroxide solution are added." A clear solution is formed. 20g of sodium borohydride are added and the whole is stirred for 5 hoursat room temperature. The solution is then cooled with ice. andhydrochloric acid is added dropwise until a pH of 3-3 has been attained.The suspension is stirred for another half hour, and then the crystalsobtained of 3-chloro-4-(1-hydroxybutyl) phenol are filtered off undersuction. They are used immediately in the crude state.

c. The moist crysta l'mass of 3-chloro-4-( l-hydroxybutyl)-phenol isadded to a solution of 200 g of sodium hydroxide in'500 ml of water, thesolution formed is heated to70 and 150 g of chloroform are addeddropwise within 2 hours. During the addition, the temperature of thereaction mixture must be 70-80. The mixture is stirred for 20 minutes at70 and then coiled to room temperature. The yellow crystal mass whichprecipitates, which consists of the sodium salt of 3-chloro-4-(1-hydroxy-butyl)-2-formyl-phenol, is filtered off undersuction. The pH of the filtrate is adjusted to 2--3 with concentratedhydrochloric acid, the filtrate is extracted twice with 100 ml of ethereach time and the combined ether extracts are washed with 100 ml ofwater, after which they are stirred for hours with 200 ml ofconcentrated sodium hydrogen sulphite solution. The crystals obtained,which consist of the'bisulphite adduct of 3-chloro-4-(1-hydroxy-butyl)-6-formyl-phenol, are filtered off under suction and washed first with 50ml of ether and then with 50 ml of water. The crystals are then slurriedin 100 ml of water, 100 ml of ether are poured in, ml of concentratedhydrochloric acid are added and the mixture is stirred for 2 hourswhereupon the, crystals dissolve. The ether phase is removed, washedwith 50 ml of water, dried over magnesium sulphate and concentrated. Theresidue consists of 6.5 g of 3-chloro-4-( l-hydroxy-butyl)-6-formylphenol, which is used in the crude state.

d. 6.5 g of crude 3-chloro- 4-(l-hydroxy-butyl)-6- forrnyl phenol aredissolved in 30 ml of methylethyl ketone, 4.0 g of potassium carbonateare added and the mixture is refluxed while stirring. 8 g ofbromomalonic acid diethyl ether are then added dropwise within 10minutes whereupon the reaction mixture is refluxed for 5 hours whilestirring. The solvent is then distilled off, the residue istaken' up in50 ml of water, concentrated hydrochloric acid is added until pH 3 isattained and the mixture is extracted twice with 100 ml of ether eachtime. The ether solutions are washed with 100 ml of water, dried over.magnesium sulphate and concentrated. A solution of 5 g of potassiumhydroxide, 5 ml of water and 50 ml of ethanol is added to the residueand the mixture is refluxed for 2 hours. 200 ml of water are then addedand the aqueous-alkaline solution is washed twice with 100 ml of ethereach time. The aqueous solution is acidified with concentratedhydrochloric acid and extracted twice with 100 ml of ether each time.The ether extracts are dried and concentrated. On standing, the residuecrystallizes and is recrystallized from benzene. In this way, 1.8 g of6- ch]oro-5-( 1 hydroxy-butyl)-benzofuran-2-carboxylic acid, M.P.194-l96, are obtained.

e. 1.8 g of 6-chlo'ro-5-( l -hydroxy-butyl)-benzofuran- 2-carboxylicacid are dissolved in 20 ml of acetone, the solution is cooled to 0 anda solution of 0.54 g of 01:0 in 0.5 ml of concentrated sulphuric acidand 1.5 m1 of water is added. The reactionrnixture is stirred for 30lized from benzene ethyl acetate and yields 1.2 g of 5-butyryl-6-chloro-benzofuran-2-carboxylic acid which melts at 2142l5. Q

. EXAMPLE 19 a. Starting from 3.6 of4-chloro-5-butyryl-benzofuran-Z-carboxylic'acid, 0.48 g ofparaformaldehyde and 1.15 g of dimethylaminehydrochloride, crude 4-chloro-S-[2 (dimethylarninomethyl) butyryll-benzofuran-Z-carboxylic acidhydrochloride is obtained analogously to example 8(b). It is convertedwith 2.0 g

of sodium acetate and 20 ml of glacial acetic acid into4-chloro-5-(2-methylene-butyryl)-benzofuran-2 carboxylic acid, M.P.l56-l58 (recrystallized from benzene/ethyl acetate).

The 4-chloro-5-butyryl-benzofuran-2-carboxylic acid used as startingmaterial is produced as follows:

b. The crude sodium salt of 3-chloro-4-(l-hydroxybutyl)-2-formyl phenolobtained in example 18(c) as side product is slurried in 200 ml ofwater, the pH is adjusted to 3 with hydrochloric acid and the slurry isextracted twice with ml of ether each time. The ether extracts arewashed with 100 ml of water, dried over magnesium sulphate and'concentrated. The residue, crude 3-chloro-4-( l-hydroxy-butyl)-2-formylphenol (30 g) is used in the crude state.

c. 8.2 g of 4-chloro-5-( l-hydroxy-butyD-benzofuran- 2-carboxylic acidare obtained analogously to example 18(d) from 30 g of3-chloro-4-(1-hydroxy-butyl)-2-formyl phenol with 20 g of potassiumcarbonate and 30 g of bromomalonic acid diethyl ester in 100 ml ofmethylethyl ketone. Recrystallized from benzene/acetic acid ethyl ester,the compound melts at 173-175.

d. 4.5 g of 4-chloro-S-butyryl-benzofuran-Z-carboxylic acid are obtainedanalogously to example 18(c) from 7.6 g'of4-chloro-5-(1-hydroxy-butyl)-benzofuran-Z-carboxylic acid in 80 ml ofacetone with a solution of 2.2 g of chromium trioxide in 6 ml of waterand 2 ml of concentrated sulphuric acid. Recrystallized frombenzene/ethyl acetate, the compound melts at EXAMPLEYZO a. 7.2 g of3,6-dimethyl--butyryl-benzofuran-2-car-' boxylic acid methyl ester and3.3 g of dimethylarnine hydrochloride are melted and the melt is stirredfor 2 hours at 140. The melt obtained consists of crude 3,6-dimethyl-5-(2-dimethylamino-methyl-butyryl)- benzofuran-Z-carboxylicacid methyl ester hydrochloride. This is refluxed for minutes with asolution of 80 ml of 1 N sodium hydroxide solution and 80 ml of ethanoland, after dilution with 300 ml of ice water, it is acidified to pH 3with concentrated hydrochloric acid. The precipitate formed is filteredofi under suction and, after drying in vacuo, it is purified bychromatographing over silica gel; The 3,6-dimethyl-5-(Z-methylene-butyryl)-benzofuran-2-carboxylic acid, whenrecrystallized from benzene/heptane, melts at 152154.

The 3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid methyl esterused as as follows:

b. 10.4 g of 3,6-dimethyl-5-butyryl-benzofuran-2- carboxylic acid areadded in portions over a period of 30 minutes to a boiling slurry of 7 gof potassium carbonate in 80 ml of acetone. Simultaneously a solution of5 ml of dimethyl sulphate in 30 ml of acetone is added to the reactionmixture from a dropping funnel. On completion of the addition, themixture is refluxed for another 3 hours while stirring, then cooled, theprecipitate is filtered off under suction and is washed with 50 ml ofacetone. The filtrate and washing liquor are combined and evaporated andthe residue is recrystallized from carbon tetrachloride/heptane. The3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid methyl ester formedmelts at 101l05.

c. The 3,6-dimethyl-5-butyryl-benzofuran-2-carboxylic acid is obtainedanalogously to example 8(b) from v3,tS-dirnethyl-benzofuran-2-carboxylicacid (cf. Fries and Finkewirth, Chem. Ann. 362, (1908) 50) with butyricacid chloride and aluminum chloride in nitrobenzene. The compound meltsat 185-l87 (recrystallized from benzene/ethyl acetate).

EXAMPLE 21 a. 0.5 g of6-methyl-5-[2-(methylthiomethyl)-butyryH-benzofuran-Z-carboxylic acidare dissolved in 5 ml of acetone, 0.5 g of dimethyl sulphate are addedand the solution is left to stand for 3 days at room temperature. Thesolvent is then evaporated under reduced pressure and the residue,consisting of crude 6-methyl-5-[Z-(dimethyl-thioniummethyl)-butyryl]-benz0furan- 2-carboxylic acidmethyl sulphate, is dissolved in 5 ml of water. 2.5 ml of saturatedsodium hydrogen carstarting material is produced bonate solution areadded to thesolution formed and the reaction mixture. is heated for 1hour in a steam bath. The cooled solution is then acidified to pH 2-3with hydrochloric acid, stirred for half an hour at room temperature andthe precipitated crystals are filtered off under suction, dried andrecrystallized from benzene. 0.3 g of6-methyl-5-[2-(methylene)-butyryl]- benzofuran-Z-carboxylic acid, M.P.14l-142, are obtained.

The 6-methyl 5-[2-(methyl-thiomethyl)-butyryl]- benzofuran-2-carboxylicacid used as starting material is produced as follows: Y

b. 6.8 g of 6-methyl-5-[Z-(dimethylaminomethyl)- butyryll-benzofuran-2carboxylic acid hydrochloride (M.P. 187-188) are dissolved in 200 ml ofwater, 4.04 g of sodium hydrogen carbonate are added in portions to thesolution and a constant stream of methyl mercaptan is bubbled throughthe mixture. While continuing the introduction of methyl mercaptan, themixture is heated to 90 and iskept for 2 hours at this temperaturewhereupon the stream of gas is cut ofi and the solution is cooled. ThepH of the solution is adjusted to 2-3 with concentrated hydrochloricacid and the precipitate formed is filtered off under suction, dried invacuo and recrystallized from a small amountof acetic acid ethyl ester.In this way, 5.2 g of 6-methyl-5-[2-(methylthiomethyl)-butyryl]-benzofuran-2-carboxylic acid, M.P. 151-152,are obtained.

EXAMPLE 22 a. 10 ml of water and 5 ml of a saturated sodium hydrogencarbonate solution are added to 6-methyl-5-[2-(methylsulphonyl-methyl)-butyryl]-benzofuran-2- carboxylic acid andthen the solution is refluxed for 1% hours. It is allowed to cool andthe solution is acidified to pH 2-3 with concentrated hydrochloric acid.The

mixture is stirred for another 30 minutes and then the precipitatedcrystals are filtered off under suction, dried in vacuo andrecrystallized from benzene. In this way, 0.5 .g Y of 6-methyl-5-(2-methylene-butyryl)- benzofuran-Z-carboxylic acid, M.P.' l41l42 areobtained. v

The6-methyl-5-[Z-mthyl-sulphonylmethyl)-butyryl]-benzofuran-2-carboxylicacid used as starting material is produced as follows:

b. 3.1 g of6-methyl-5-[2-(methylthiomethyl)-butyryl]-benzofuran-2-carboxylic acid(production see example 21) are slurried in 15 ml of glacial acetic acidand 3.6 g of 40 percent peracetic acid are so added dropwise to themixture while cooling with ice that the reaction temperature remainsbetween 15 and 20. The reaction mixture is then stirred for 15 hours atroom temperature and the precipitated crystal mass is filtered off undersuction. Recrystallized from ethyl acetate/dioxane, 2.8 g of6-methyl-5-[2-(methylsulphonylmethyl)-butyryl]benzofuran-Z-carboxylicacid, MP. 20l203, are obtained.

EXAMPLE 23 a. A solution of 6-methyl-5-(2-methylene-butyryl)-benzofuran-Z-carboxylic acid methyl ester in 5 ml of ethanol is heatedto reflux temperature, 2 ml of 1N sodium hydroxide solution are addedand the mixture is refluxed for another minute whereupon it is dilutedwith ml of ice water. The solution is then washed with 50 ml of ether,the pH of the aqueous-alkaline phase is adjusted to 2-3 withhydrochloric acid and the mixture is stirred for 30 minutes. Theprecipitate formed is filtered ofl under suction, dried in vacuo andrecrystallized from benzene. In this way, 0.4 g of 6- methyl-5-(2methylene-butyryl)-benzofuran-2-carboxylic acid, M.P. l41-142, areobtained. 1

The 6-methyl-5-(2-methylene-butyryl)-benzofuran- 2-carboxylic acidmethyl ester used as starting material canbe producedasfollowsz I 1 b.5.0 g of anhydrous potassium carbonate are slur ried-in 20 ml ofacetone'and the slurry, is brought to reflux temperature. A solution of7.5 g of 6-methyl-5- butyryl-benzofurari-2-carboxylicacid and 3.75 mlofdirnethyl sulphate in 70 ml of acetone is added dropwise to thissuspension within minutes whereupon the reaction mixture is refluxed foranother hour and cooled. Insoluble salts are then filtered ofl, theacetone solution is concentrated and the residue is recrystallizedfrommethanol. 7.3 g of 6-methyl-5-butyrylbenzofuran-2-carboxylic acid methylester, M.P. 9l-92, are obtained in this way.

c. 5.5 g of the 6-methyl-5-butyryl-benzofuran-2-carboxylic acid methylester. produced in b) above are refluxed for 24 hours withv 1.2 g ofparaformaldehyde and 3.2 g of dimethylamine hydrochloridein 12 ml ofmethanol. The methanol is then evaporated, 30 ml of acetic acid ethylester are added to the residue which is then left 'to stand for 2 daysin a refrigerator. The crystal mass so obtained is then filtered off andrecrystallized from acetonitrile whereupon 2.4 g of 6-methyl-5-[2-(dimethylaminomethyD-butyryl]- benzofuran-Z-car'boxylic acidmethyl hydrochloride, M.P. 176-178, are obtained,

d. 1.2 g v of the 6 -methyl-5-[ 2-'(dimethylaminomethyl)-butyryl]-benzofuran-2 carboxylic acid methyl esterhydrochloride are refluxed for 2 hours with 1.2- g of sodium acetate andml of glacial acetic acid. The glacial acetic acid is then evaporated ina rotary evaporator and the residue is distributed between 100 ml ofwater and 100 ml of ether. After washing the ether phase with 100 ml ofwater, it is removed, dried with 100 ml of saturated sodium hydrogencarbonate solution overmagnesium sulphate and concentrated. The residueis recrystallized from methanol and yields 0.6 g of 6 -methyl-5-(2-methylene-butyryl)-benzofuran 2-carboxylic acid methyl ester, M.P.85-86.

EXAMPLE 24 ester a separating funnel, the organic phase is removed,washed with 50 ml of water, dried over magnesium sulphate andconcentrated. The residue is recrystallized from benzene and6-methyl-5-(2-methylenepropionyl')-benzofuran-2-carboxylic acid, M.P. 18e st arting material, methyl-propionyl)+benzofuran-2-carboxylic acid, isproduced'as follows:

b. 3.0 g of 6-methyl-5-isobutyryl-benzofuran-2-carboxylic acid aredissolved-in ml of glacial acetic acid and 0.7.ml of bromine are addeddropwise within 15 minutes to this solution at 50. The whole is stirredfor another 15 minutes at the same temperature, after which the glacialacetic acid is evaporated in a rotary evaporator and the residue isrecrystallized from ethyl acetate/dioxane. 3.65. g of-6-methyl-5-(2-bromo-2- methyl-propionyl) -benzofuran-2-carboxylic acid,M.P.

23 l-233, are obtained in this way.

c. The 6-methyl-5-isobutyryl-benzofuramZ-carboxylic acid is producedanalogously to example 8(b) from 6-methyl-benzofuran- 2-carboxylic acid(cf. K. von Auwers, Ann. 'Chem. 408, (1915) 255) with isobutyrylchloride and aluminum chloride in nilrobenzene. lt

' melts at l74 -l 75 (recrystallized from methylethyl containing 100 mgof active substance. If desired, the

tablets can be grooved for better adaptation of the dosage.

EXAMPLE 26 A granulate is produced from 1,000 g of 5-(2-methylene-butyryl)-benzofuran-2-carboxylic acid, 379 g of lactose andthe aqueous solution of 6 g of gelatine. After drying, the granulate ismixed with 10 g of colloidal silicon dioxide, 40 g of talcum, g ofpotato starch and 5 g of magnesium stearate and the mixture is pressedinto 10,000 dragee cores. These are then coated with a concentratedsyrup consisting of 533.5 g of crystallized saccharose, 20 g of shellac,g of gum arabic, 250 g of talcum, 20 g of colloidal silicon dioxide and1.5 g of dyestuff, and dried. The dragees obtained each weigh 240 mg andcontain mg'of active substance.

What we claim is:

1. 4-chloro-5-(Z-methylene-butyryl)-indole-2-carboxylic acid.

6-methyl-5-( 2-bromo-2-

